Abstract
Simple SummaryThe European trial SIOP PNET5 MB was initiated in 2014 and will remain open to recruitment until 2022. It is the first European trial using clinical, histological, and molecular parameters to stratify treatments for childhood medulloblastoma, based on disease risk. In the standard-risk stratum, a randomized intensification of carboplatin concomitant to radiotherapy is investigated. In the favourable-risk stratum, defined by localized WNT subgroup disease, reduction of craniospinal radiotherapy intensity (from 24 to 18 Gy) and reduced maintenance chemotherapy is investigated for children <16 years old at diagnosis. Two additional exploratory strata (WNT-HR and SHH-TP53) have been implemented during the trial. The use of biological parameters for stratification has proven feasible in a prospective multicentre setting, and may improve future risk-adapted treatment. The primary endpoint is 3-year event-free survival. Late effects on hearing, endocrine- and neurologic function, alongside health-related quality of life (e.g., health status, behavioural outcomes), are secondary endpoints.Background. SIOP PNET5 MB was initiated in 2014 as the first European trial using clinical, histological, and molecular parameters to stratify treatments for children and adolescents with standard-risk medulloblastoma. Methods. Stratification by upfront assessment of molecular parameters requires the timely submission of adequate tumour tissue. In the standard-risk phase-III cohort, defined by the absence of high-risk criteria (M0, R0), pathological (non-LCA), and molecular biomarkers (MYCN amplification in SHH–MB or MYC amplification), a randomized intensification by carboplatin concomitant with radiotherapy is investigated. In the LR stratum for localized WNT-activated medulloblastoma and age <16 years, a reduction of craniospinal radiotherapy dose to 18 Gy and a reduced maintenance chemotherapy are investigated. Two additional strata (WNT-HR, SHH-TP53) were implemented during the trial. Results. SIOP PNET5 MB is actively recruiting. The availability of adequate tumour tissue for upfront real-time biological assessments to assess inclusion criteria has proven feasible. Conclusion. SIOP PNET5 MB has demonstrated that implementation of biological parameters for stratification is feasible in a prospective multicentre setting, and may improve risk-adapted treatment. Comprehensive research studies may allow assessment of additional parameters, e.g., novel medulloblastoma subtypes, and identification and validation of biomarkers for the further refinement of risk-adapted treatment in the future.
Highlights
Introduction and Status of Knowledge WhenSIOP PNET5 MB Was PlannedMedulloblastoma is a highly cellular malignant embryonal neoplasm [1]
The WNT-active medulloblastoma criteria clearly define a subgroup with good prognosis, and, at the time of SIOP PNET5 MB design, β-catenin status had been shown to be an independent marker of favourable clinical outcome across independent clinical trials-based biological studies [4,27], including the PNET4 study for children younger than 16 years [29]
The eligibility criteria and risk-stratification schemes for SIOP PNET5 MB are based on contemporary understanding of the biological features of medulloblastoma and their clinical relevance
Summary
Medulloblastoma is a highly cellular malignant embryonal neoplasm [1]. It is the most common malignant brain tumour in children, accounting for 15 to 20% of all childhood primary central nervous system (CNS) neoplasms. Decreased prognosis was explained by an unwillingness to apply dose-intense radiotherapy in this young age group, as this causes severe damage to the developing brain [15] Due to these factors, infants were not considered to be ‘standard risk’ patients, and could not be included into the trial SIOP PNET5 MB. In PNET4, the outcome of patients whose scans had not been centrally reviewed was found to be worse than of patients in which central review of MRI scans of brain and spine had taken place [10] This suggested that quality assurance of imaging was a relevant tool for keeping the group of included patients clear of patients with falsely negative metastasis staging. More recent data suggested that the histological subtype of medulloblastoma as well as biological factors influence clinical behaviour, and could be used to optimize treatment stratification [22–24]
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